JP2013147480A - Pharmaceutical composition and medicinal cosmetic using the same - Google Patents
Pharmaceutical composition and medicinal cosmetic using the same Download PDFInfo
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- JP2013147480A JP2013147480A JP2012011342A JP2012011342A JP2013147480A JP 2013147480 A JP2013147480 A JP 2013147480A JP 2012011342 A JP2012011342 A JP 2012011342A JP 2012011342 A JP2012011342 A JP 2012011342A JP 2013147480 A JP2013147480 A JP 2013147480A
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Abstract
Description
本発明は、医薬組成物及びこれを用いた薬用化粧品に関する。 The present invention relates to a pharmaceutical composition and a medicated cosmetic using the same.
細菌、ウィルス等の感染や物理的な傷害等の外的要因による細胞障害（外因性障害）、又は精神的ストレスや血行不良等の内的要因による細胞障害（内因性障害）の治療には、創傷治療薬、抗炎症薬等の医薬組成物が用いられている。
細胞障害の治療に用いる医薬組成物として、生体組織（以下、単に組織ということがある）に対し修復作用を有する多糖類やオリゴ糖を含有するものが提案されている。例えば、哺乳動物に対して生理活性を有し且つ糖タンパク質糖鎖及び糖脂質糖鎖を構成する単糖を一種以上構成糖として含む多糖類及び／又はそのオリゴ糖を配合・混合してなる組織・細胞障害のための予防・修復剤が提案されている（例えば、特許文献１）。
一方、循環虚脱、低血糖時の糖質補給、高カリウム血症、非経口的なエネルギー及び水補給を目的とした注射剤に含有されるグルコースは、組織の修復を遅延させると報告されている（例えば、非特許文献１）。
For the treatment of cell damage due to external factors such as bacterial and viral infections and physical injury (exogenous disorders), or cellular damage due to internal factors such as mental stress and poor circulation (intrinsic disorders) Pharmaceutical compositions such as wound healing drugs and anti-inflammatory drugs are used.
As a pharmaceutical composition used for the treatment of cell damage, a composition containing a polysaccharide or oligosaccharide having a repairing action on a living tissue (hereinafter sometimes simply referred to as a tissue) has been proposed. For example, a tissue comprising a polysaccharide and / or an oligosaccharide thereof having physiological activity for mammals and containing one or more monosaccharides constituting glycoprotein sugar chains and glycolipid sugar chains as constituent sugars A prophylactic / restoring agent for cell damage has been proposed (for example, Patent Document 1).
On the other hand, glucose contained in injections intended for circulatory collapse, carbohydrate supplementation during hypoglycemia, hyperkalemia, parenteral energy and water supplementation has been reported to delay tissue repair (For example, Non-Patent Document 1).
また、組織の修復を目的とした医薬組成物としては、ステロイド剤を含有するものがある。ステロイド剤は、ステロイド骨格を有する化合物であり、強力な抗炎症作用、免疫抑制作用等を示す物質として、広範な薬物療法に用いられている。
ステロイド剤は、元々、生体内の臓器で産生される化合物であり、一般に、副腎皮質ステロイドを指す。ステロイド剤は、その適用範囲が広く、適応症が最も多い薬剤の一つとして知られている。ステロイド剤の適用対象となる疾患としては、例えば、気管支喘息、アトピー性皮膚炎、花粉症、アレルギー性鼻炎、突発性難聴、関節リュウマチ、膠原病、ネフローゼ症候群、潰瘍性大腸炎等が挙げられる。
Some pharmaceutical compositions intended for tissue repair contain steroids. A steroid agent is a compound having a steroid skeleton, and is used in a wide range of drug therapy as a substance exhibiting a strong anti-inflammatory action, an immunosuppressive action and the like.
A steroid agent is a compound originally produced in an organ in a living body, and generally refers to a corticosteroid. Steroids are known as one of the most widely applied drugs with a wide range of applications. Examples of diseases to which steroids are applied include bronchial asthma, atopic dermatitis, hay fever, allergic rhinitis, sudden hearing loss, rheumatoid arthritis, collagen disease, nephrotic syndrome, ulcerative colitis and the like.
炎症は、プロスタグランジンやロイコトリエン等の物質をメディエーターとして誘発される。ステロイド剤は、細胞の核内に取り込まれ、遺伝子を活性化することによりタンパク質リポコルチンを合成し、タンパク質リポコルチンがホスホリパーゼＡ２を阻害する。この結果、プロスタグランジンとロイコトリエンの合成を抑制することで抗炎症作用を発揮する。加えて、ステロイド剤は炎症性サイトカイン遺伝子、及びプロスタグランジンの生合成に関わるシクロオキシゲナーゼ−２（ＣＯＸ−２）遺伝子の発現を制御すると考えられており、これがステロイド剤の抗炎症作用の主な作用機序として認識されている。 Inflammation is induced using substances such as prostaglandins and leukotrienes as mediators. A steroid agent is taken into the nucleus of a cell and synthesizes a protein lipocortin by activating a gene, and the protein lipocortin inhibits phospholipase A2. As a result, it suppresses the synthesis of prostaglandins and leukotrienes to exert an anti-inflammatory effect. In addition, steroids are thought to regulate the expression of inflammatory cytokine genes and cyclooxygenase-2 (COX-2) genes involved in prostaglandin biosynthesis, which are the main effects of anti-inflammatory effects of steroids It is recognized as a mechanism.
ステロイド剤は、長期にわたり使用されたり、頻繁に使用されたりすると、生体内に十分量が存在することとなる。生体内のステロイド量が高まると、生体内でのステロイド剤の産生が低下するという問題がある。加えて、ステロイド剤は、正常細胞の増殖を抑制して（増殖抑制作用）、細胞組織の修復を遅延させやすいという問題がある。 When a steroid is used over a long period of time or used frequently, a sufficient amount will exist in the living body. When the amount of steroid in the living body increases, there is a problem that the production of the steroid agent in the living body decreases. In addition, the steroid agent has a problem that it suppresses the growth of normal cells (proliferation inhibitory action) and tends to delay the repair of the cell tissue.
こうした問題に対し、ステロイド剤と黄ごん由来組成物とを併用する抗炎症治療薬が提案されている（例えば、特許文献２）。特許文献２の発明によれば、ステロイド剤の抗炎症作用を維持しつつ、正常細胞に対するステロイド剤のアポトーシス作用を抑えられる。
In order to deal with such problems, an anti-inflammatory therapeutic agent using a combination of a steroid agent and a composition derived from corn is proposed (for example, Patent Document 2). According to the invention of
しかしながら、組織の修復をより一層促進したり、より一層効果的に細胞障害を予防できる医薬組成物が求められている。
そこで、本発明は、細胞障害を効果的に予防でき、各種障害を受けた組織の修復を促進できる医薬組成物を目的とする。
However, there is a need for a pharmaceutical composition that can further promote tissue repair or more effectively prevent cell damage.
Accordingly, the present invention is directed to a pharmaceutical composition that can effectively prevent cell damage and can promote the repair of tissues damaged by various kinds of damage.
細胞の核内に普遍的に存在する非ヒストンタンパク質であるＨｉｇｈ Ｍｏｂｉｌｉｔｙ Ｇｒｏｕｐ Ｂｏｘ１（ＨＭＧＢ１）は、核内でタンパク質複合体を形成しクロマチン構造の安定性を保持し、様々な遺伝子の転写を制御したり、ＤＮＡ損傷を修復したりするのに関わっている。ＨＭＧＢ１は、通常、細胞の核内に存在するが、細胞が活性化されたり、細胞が壊死したりすると、細胞外に放出される。細胞外に放出されたＨＭＧＢ１は、炎症細胞を活性化したり、組織を保護したり、組織を修復したりする。例えば、ＨＭＧＢ１は、線維芽細胞、上皮細胞、血管内皮細胞、骨格筋細胞、心筋細胞や幹細胞等を活性化し、それらの増殖や遊走を促進する。
本発明者らは、鋭意検討した結果、意外にもグルコースがＨＭＧＢ１の産生を促進し、ＨＭＧＢ１の細胞外への放出を誘導し、正常細胞の増殖や遊走を高め、組織の修復を促進できるとの知見を得て、本発明に至った。
High Mobility Group Box 1 (HMGB1), a non-histone protein that is ubiquitously present in the cell nucleus, forms a protein complex in the nucleus, maintains the stability of chromatin structure, and regulates the transcription of various genes. And is involved in repairing DNA damage. HMGB1 is usually present in the nucleus of the cell, but is released to the outside when the cell is activated or necrotic. HMGB1 released outside the cells activates inflammatory cells, protects tissues, and repairs tissues. For example, HMGB1 activates fibroblasts, epithelial cells, vascular endothelial cells, skeletal muscle cells, cardiomyocytes and stem cells, and promotes their proliferation and migration.
As a result of intensive studies, the present inventors have unexpectedly found that glucose can promote the production of HMGB1, induce the release of HMGB1 to the outside of the cells, increase the proliferation and migration of normal cells, and promote tissue repair. As a result, the present invention was achieved.
即ち、本発明の医薬組成物は、グルコースを含有することを特徴とする。
さらに、ステロイド剤を含有してもよく、前記グルコース／前記ステロイド剤で表されるモル比が１０〜１０５であることが好ましい。
That is, the pharmaceutical composition of the present invention is characterized by containing glucose.
Furthermore, may contain steroid, it is preferable molar ratio represented by the glucose / the steroid agent is 10 to 10 5.
本発明の薬用化粧品は、本発明の前記医薬組成物を含有することを特徴とする。 The medicated cosmetic of the present invention is characterized by containing the pharmaceutical composition of the present invention.
本発明によれば、細胞障害を効果的に予防でき、各種障害を受けた組織の修復を促進できる。 According to the present invention, cell damage can be effectively prevented, and repair of tissues that have received various kinds of damage can be promoted.
（医薬組成物）
本発明の医薬組成物は、組織修復促進剤としてグルコースを含有するものである。
医薬組成物としては、例えば、アトピー性皮膚炎、気管支喘息、関節リウマチや膠原病等の自己免疫疾患の治療薬；ネフローゼ症候群、潰瘍性大腸炎、肝炎、膵炎、甲状腺炎、感冒等の臓器炎症等の疾患の治療薬等の抗炎症薬；やけど、傷、床ずれ、にきび、あせも、しもやけ等の創傷の治療薬（創傷治療薬）等が挙げられ、特に抗炎症薬、創傷治療薬において、本発明の効果が顕著である。
(Pharmaceutical composition)
The pharmaceutical composition of the present invention contains glucose as a tissue repair promoter.
Examples of pharmaceutical compositions include therapeutic agents for autoimmune diseases such as atopic dermatitis, bronchial asthma, rheumatoid arthritis and collagen disease; organ inflammation such as nephrotic syndrome, ulcerative colitis, hepatitis, pancreatitis, thyroiditis, cold Anti-inflammatory drugs such as remedies for diseases such as burns, wounds, bedsores, acne, bruises, bruises, etc., especially for anti-inflammatory drugs and wound remedies. The effect of the invention is remarkable.
医薬組成物の剤形としては、特に限定されず、例えば、錠剤、顆粒剤、細粒剤、散剤、カプセル剤、丸剤、液剤、乳剤、懸濁剤、シロップ剤及びトローチ剤等の経口剤；軟膏、ローション、クリーム、エアゾール剤等の経皮吸収剤；注射剤、点眼剤及び坐剤等の非経口剤が挙げられ、中でも、軟膏等の経皮吸収剤において、本発明の効果が顕著に表れる。なお、注射剤は、安定性の観点から、液剤がバイアル等に充填された後、凍結乾燥処理により水分が除去され、使用直前に、凍結乾燥物が生理食塩水等に分散されて、液剤に調製されたものでもよい。 The dosage form of the pharmaceutical composition is not particularly limited, and for example, oral preparations such as tablets, granules, fine granules, powders, capsules, pills, solutions, emulsions, suspensions, syrups, and lozenges. ; Transdermal absorbents such as ointments, lotions, creams, aerosols; and parenteral agents such as injections, eye drops, and suppositories. Among them, the effects of the present invention are remarkable in transdermal absorbents such as ointments. Appear in In addition, from the viewpoint of stability, an injection is prepared by filling a vial or the like with water, removing water by lyophilization, and dispersing the lyophilized product in physiological saline or the like immediately before use. It may be prepared.
＜グルコース＞
本発明の医薬組成物は、組織修復促進剤としてグルコースを含有することで、細胞でのＨＭＧＢ１の産生を促進し、細胞からのＨＭＧＢ１の放出を誘導して、組織の修復を促進できる。
組織修復促進剤は、細胞の増殖を促進し、障害細胞を含む組織の自己修復を図るものである。
医薬組成物中のグルコースの含有量は、医薬組成物の剤形、用途、用法等を勘案して決定でき、例えば、経皮吸収剤であれば、０．１〜５ｍｏｌ／Ｌが好ましく、１〜３ｍｏｌ／Ｌが好ましい。上記下限値以上であれば、経皮吸収されたグルコースによって、ＨＭＧＢ１の産出と放出とをより促進して、細胞障害をより良好に予防し、組織の修復を促進できる。上記上限値以下であれば、グルコースが医薬組成物中に均一に分散して、細胞障害をより良好に予防し、組織の修復を十分に促進できる。
また、例えば、注射剤であれば、１〜１０００ｍＭ／Ｌが好ましく、１０〜１００ｍＭ／Ｌがより好ましい。上記範囲内であれば、ＨＭＧＢ１の産生と放出とをより促進して、細胞障害をより良好に予防し、組織の修復をより促進できる。
<Glucose>
By containing glucose as a tissue repair promoter, the pharmaceutical composition of the present invention can promote the production of HMGB1 in cells, induce the release of HMGB1 from cells, and promote tissue repair.
The tissue repair promoter promotes cell proliferation and self-repairs a tissue containing damaged cells.
The content of glucose in the pharmaceutical composition can be determined in consideration of the dosage form, use, usage, etc. of the pharmaceutical composition. For example, 0.1 to 5 mol / L is preferable for a transdermal absorbent. ˜3 mol / L is preferred. If it is above the above lower limit, transdermally absorbed glucose can further promote the production and release of HMGB1, better prevent cell damage, and promote tissue repair. If it is below the above upper limit, glucose can be uniformly dispersed in the pharmaceutical composition, thereby preventing cell damage better and sufficiently promoting tissue repair.
For example, in the case of an injection, 1 to 1000 mM / L is preferable, and 10 to 100 mM / L is more preferable. Within the above range, production and release of HMGB1 can be further promoted, cell damage can be better prevented, and tissue repair can be further promoted.
＜ステロイド剤＞
医薬組成物は、ステロイド剤を含有してもよい。医薬組成物は、ステロイド剤を含有することで、抗炎症作用等の優れた作用を発揮できる。加えて、ステロイド剤を含有する医薬組成物において、本発明の効果がより顕著に発揮される。特に、ステロイド剤の抗炎症作用等の薬効が期待される抗炎症薬等の医薬組成物において、ステロイド剤の増殖抑制作用はグルコースにより顕著に軽減される。
<Steroids>
The pharmaceutical composition may contain a steroid agent. The pharmaceutical composition can exhibit excellent effects such as an anti-inflammatory effect by containing a steroid agent. In addition, in the pharmaceutical composition containing a steroid agent, the effect of the present invention is more remarkably exhibited. In particular, in a pharmaceutical composition such as an anti-inflammatory drug expected to have a medicinal effect such as an anti-inflammatory action of a steroid agent, the growth inhibitory action of the steroid agent is significantly reduced by glucose.
ステロイド剤としては、医薬組成物の用途等を勘案して決定でき、例えば、酢酸コルチゾン、ヒドロコルチゾン、コハク酸ヒドロコルチゾンナトリウム、プレドニゾロン、メチルプレドニゾロン、コハク酸メチルプレドニゾロンナトリウム、トリアムシノロン、トリアムシノロンアセトニド、デキサメサゾン、パルミチン酸デキサメサゾン、ベタメタゾン、酢酸パラメタゾン、酢酸フルドロコルチゾン、酢酸ハロプレドン等が挙げられ、中でも、本発明の効果を顕著に発揮させる観点から、ヒドロコルチゾン、プレドニゾロン、デキサメサゾン及びベタメタゾンから選択される少なくとも１種が好ましい。これらのステロイド剤は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。 The steroid can be determined in consideration of the use of the pharmaceutical composition, for example, cortisone acetate, hydrocortisone, hydrocortisone sodium succinate, prednisolone, methylprednisolone, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetonide, dexamethasone, palmitin Examples include acid dexamethasone, betamethasone, parameterzone acetate, fludrocortisone acetate, halopredone acetate, etc. Among them, from the viewpoint of remarkably exerting the effects of the present invention, at least one selected from hydrocortisone, prednisolone, dexamethasone and betamethasone is preferable. . These steroid agents may be used alone or in combination of two or more.
ヒドロコルチゾンは、生理的コルチコステロイドであり、作用時間が比較的短いものである。
プレドニゾロンは経口投与剤として汎用されており、ヒドロコルチゾンのステロイド骨格の１，２位に二重結合を有し、ヒドロコルチゾンよりも強力な抗炎症作用を持つ。
デキサメサゾンは、プレドニゾロンの９位にフッ素、１６位にメチル基が導入された合成グルココルチコイドであり、プレドニゾロンよりも強力な抗炎症作用、抗アレルギー作用を発揮する。ベタメタゾンは、デキサメサゾンの異性体であり、長時間作用する強力なステロイド剤として知られている。
Hydrocortisone is a physiological corticosteroid and has a relatively short duration of action.
Prednisolone is widely used as an oral administration agent, has a double bond at
Dexamethasone is a synthetic glucocorticoid in which fluorine is introduced at the 9th position of prednisolone and a methyl group is introduced at the 16th position, and exhibits stronger anti-inflammatory and antiallergic effects than prednisolone. Betamethasone is an isomer of dexamethasone and is known as a long acting steroid.
医薬組成物中のステロイド剤の含有量は、医薬組成物の用途や、ステロイド剤の種類を勘案して決定でき、例えば、０．０５〜０．１質量％とされる。上記範囲内であれば、ステロイド剤の抗炎症作用等の作用が十分に発揮されやすく、ステロイド剤の増殖抑制作用がグルコースによって、より良好に軽減される。 The content of the steroid agent in the pharmaceutical composition can be determined in consideration of the use of the pharmaceutical composition and the type of the steroid agent, and is, for example, 0.05 to 0.1% by mass. If it is in the said range, effects, such as an anti-inflammatory effect of a steroid agent, will be fully exhibited easily, and the growth inhibitory effect of a steroid agent will be reduced more favorably by glucose.
医薬組成物中、グルコース／ステロイド剤で表されるモル比（以下、グルコース／ステロイド比ということがある）は、医薬組成物の用途やステロイド剤の種類を勘案して決定でき、１０〜１０５が好ましく、１０２〜１０４がより好ましく、１０２〜１０３がさらに好ましい。上記範囲内であれば、ステロイド剤の増殖抑制作用がより軽減されて、組織の修復がより促進されやすくなる。加えて、上記範囲内であれば、ステロイド剤の抗炎症作用等の作用が十分に発揮されやすい。 In the pharmaceutical composition, the molar ratio represented by glucose / steroids (hereinafter sometimes referred to as glucose / steroid ratio) can be determined in consideration of the type of application and steroids pharmaceutical composition, 10 to 10 5 Is preferable, 10 2 to 10 4 is more preferable, and 10 2 to 10 3 is more preferable. Within the above range, the growth inhibitory action of the steroid agent is further reduced, and tissue repair is more easily promoted. In addition, if it is within the above range, the anti-inflammatory action and the like of the steroid agent are sufficiently exerted.
＜任意成分＞
医薬組成物は、グルコース及びステロイド剤に加え、必要に応じて、任意成分（特に医薬任意成分ということがある）を含有できる。医薬任意成分としては、例えば、薬理学的に許容される塩、賦形剤、増粘剤、担体、香料、色素等が挙げられる。これらの医薬任意成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
<Optional component>
In addition to glucose and a steroid, the pharmaceutical composition can contain an optional component (in particular, it may be referred to as a pharmaceutical optional component) as necessary. Examples of pharmaceutical optional components include pharmacologically acceptable salts, excipients, thickeners, carriers, fragrances, and pigments. These pharmaceutical arbitrary components may be used alone or in combination of two or more.
薬理学的に許容される塩としては、慣用の無毒性の塩、即ち酸付加塩及び各種塩基との塩が挙げられ、例えば、塩酸塩、硝酸塩、硫酸塩等の無機酸塩；酢酸塩、クエン酸塩、フマル酸塩、酒石酸塩等の有機酸塩；メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等のスルホン酸塩、アラニン塩、ロイシン塩、グルタミン酸塩等のアミノ酸塩；アルカリ金属塩（例えば、ナトリウム塩、カリウム塩等）及びアルカリ土類金属塩（例えば、マグネシウム塩、カルシウム塩等）等の無機塩基塩；トリエチルアミン塩、ピリジン塩、ピコリン塩、エタノールアミン塩、トリエタノールアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩等の有機アミン塩等が挙げられる。これらの塩は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。このような塩を含有すると、結晶化が容易なためである。 Examples of the pharmacologically acceptable salt include conventional non-toxic salts, that is, acid addition salts and salts with various bases, for example, inorganic acid salts such as hydrochloride, nitrate, sulfate, acetate, Organic acid salts such as citrate, fumarate and tartrate; sulfonates such as methanesulfonate and p-toluenesulfonate; amino acid salts such as alanine, leucine and glutamate; alkali metal salts ( For example, sodium salts, potassium salts, etc.) and inorganic base salts such as alkaline earth metal salts (eg, magnesium salts, calcium salts, etc.); triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexyl Examples thereof include amine salts and organic amine salts such as N, N′-dibenzylethylenediamine salt. These salts may be used individually by 1 type, and may be used in combination of 2 or more type. This is because when such a salt is contained, crystallization is easy.
賦形剤は、医薬組成物の剤形に応じて適宜選択でき、例えば、蒸留水、イオン交換水、純水等の水、メタノール、エタノール等の炭素数１〜６の低級アルコール、グリセリン等の液体の賦形剤；乳糖、デンプン、デキストリン、白糖等の固体の賦形剤等が挙げられる。これらの賦形剤は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。 The excipient can be appropriately selected according to the dosage form of the pharmaceutical composition, for example, water such as distilled water, ion-exchanged water, pure water, etc., lower alcohols having 1 to 6 carbon atoms such as methanol and ethanol, glycerin and the like. Liquid excipients; solid excipients such as lactose, starch, dextrin, sucrose, etc. These excipients may be used alone or in combination of two or more.
増粘剤は、医薬組成物の剤形に応じて適宜選択でき、例えば、ゼラチン、キサンタンガム、カラギーナン等が挙げられる。これらの増粘剤は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。 The thickener can be appropriately selected according to the dosage form of the pharmaceutical composition, and examples thereof include gelatin, xanthan gum, carrageenan and the like. These thickeners may be used individually by 1 type, and may be used in combination of 2 or more type.
医薬組成物の用法としては、例えば、疾患の種類等に応じて適宜決定される。
例えば、疾患がアトピー性皮膚炎、切り傷や擦り傷等の皮膚の創傷等である場合、経皮吸収剤である医薬組成物を直接患部に塗布する方法等が挙げられる。
また、疾患が口腔内や胃腸である場合、医薬組成物を経口剤として経口投与する方法、医薬組成物を注射剤として患部組織に注入する方法等が挙げられる。もしくは、例えば、上部内視鏡下で患部を医薬組成物で洗浄したり、患部に医薬組成物を塗布することにより、粘膜再生を促してもよい。これにより、健全な粘膜を形成でき、自然治癒を漸増させ、粘膜侵襲を防ぐことができる。さらに、医薬組成物を胃粘膜に塗布することで、胃粘膜の再生を促し、上皮組織を修復できる。上皮細胞の修復、即ち、正常細胞の活性化を促すことで、癌化細胞等の異常細胞の増殖を抑え、組織の正常化を誘導できる。
また、疾患が花粉症等、鼻・眼粘膜部の疾患である場合、医薬組成物を患部に塗布する方法が挙げられる。医薬組成物を鼻・眼粘膜部に塗布すると、鼻・眼粘膜部は、修復され、かつ粘膜層に強固なバリアを形成する。このため、鼻・眼粘膜部にアレルゲンが多数付着してもアレルギー反応を押さえ、鼻詰まりが生じたり、鼻汁又は涙が多量に分泌されたりするのを解消できる。
また、あるいは、疾患が風邪等のウィルスや細菌の感染による上気道粘膜の炎症（感冒）である場合、医薬組成物を点鼻したり吸入させたりする方法が挙げられる。これにより、上気道粘膜の炎症を抑え、上気道粘膜を修復して再生して感染進行を抑制でき、かつ自然免疫応答の賦活化を促進できる。
As usage of a pharmaceutical composition, it determines suitably according to the kind etc. of disease, for example.
For example, when the disease is atopic dermatitis, a skin wound such as a cut or an abrasion, and the like, a method of directly applying a pharmaceutical composition as a transdermal absorbent to the affected area can be mentioned.
In addition, when the disease is in the oral cavity or gastrointestinal tract, a method of orally administering the pharmaceutical composition as an oral preparation, a method of injecting the pharmaceutical composition into an affected tissue as an injection, and the like can be mentioned. Alternatively, for example, the affected part may be washed with a pharmaceutical composition under the upper endoscope, or the mucous membrane regeneration may be promoted by applying the pharmaceutical composition to the affected part. Thereby, a healthy mucous membrane can be formed, natural healing can be gradually increased, and mucosal invasion can be prevented. Furthermore, by applying the pharmaceutical composition to the gastric mucosa, regeneration of the gastric mucosa is promoted, and the epithelial tissue can be repaired. By promoting repair of epithelial cells, that is, activation of normal cells, proliferation of abnormal cells such as cancerous cells can be suppressed and normalization of tissues can be induced.
In addition, when the disease is a disease of the nasal or ocular mucosa such as hay fever, a method of applying a pharmaceutical composition to the affected area can be mentioned. When the pharmaceutical composition is applied to the nose / ocular mucosa, the nose / ocular mucosa is repaired and forms a strong barrier in the mucosal layer. For this reason, even if a large number of allergens adhere to the nose / ocular mucosa, the allergic reaction can be suppressed, and nasal clogging or nasal discharge or tear secretion can be eliminated.
Alternatively, when the disease is inflammation (cold) of the upper respiratory tract mucosa caused by infection with a virus such as a cold or bacteria, a method of instilling or inhaling the pharmaceutical composition can be mentioned. Thereby, inflammation of the upper airway mucosa can be suppressed, the upper airway mucosa can be repaired and regenerated to suppress the progression of infection, and activation of the innate immune response can be promoted.
医薬組成物の投与量は、患者の年齢、体重、疾患の種類・程度、投与方法等に応じて適宜決定される。例えば、医薬組成物がステロイド剤を含有する場合、現在、市場において用いられている医薬品中のステロイド剤と同程度の量のステロイド剤を含むように投与できる。また、本発明の医薬組成物は、ステロイド剤による正常細胞に対する修復抑制作用を軽減できるため、通常用いられている量よりも多い量のステロイド剤を含むように投与されてもよい。 The dosage of the pharmaceutical composition is appropriately determined according to the patient's age, weight, type / degree of disease, administration method, and the like. For example, when a pharmaceutical composition contains a steroid, it can be administered so as to contain a steroid in the same amount as the steroid in pharmaceuticals currently used on the market. Moreover, since the pharmaceutical composition of this invention can reduce the repair inhibitory effect with respect to a normal cell by a steroid agent, you may administer so that the amount of steroid agents larger than the normally used amount may be included.
（薬用化粧品）
本発明の薬用化粧品は、本発明の医薬組成物を含有するものである。本発明の薬用化粧品は、例えば、ローション、クリーム、乳液、ファンデーション等であって、皮膚疾患の予防を目的とするものである。なお、薬用化粧品は、日本国の薬事法に定められた医薬部外品に分類されるものである。
(Medicinal cosmetics)
The medicated cosmetic of the present invention contains the pharmaceutical composition of the present invention. The medicinal cosmetics of the present invention are, for example, lotions, creams, emulsions, foundations, etc., and are intended for the prevention of skin diseases. Medicinal cosmetics are classified as quasi-drugs stipulated in the Japanese Pharmaceutical Affairs Law.
薬用化粧品中の医薬組成物の含有量は、薬用化粧品の用途や剤形等を勘案して決定でき、例えば、薬用化粧品中のグルコース濃度が、好ましくは１〜１０００ｍＭ／Ｌ、より好ましくは１０〜１００ｍＭ／Ｌとなる量とされる。上記範囲内であれば、ＨＭＧＢ１の産生と放出とをより促進して、細胞障害をより良好に予防し、組織の修復をより促進できる。また、ステロイド剤を含有する薬用化粧品を含有する場合、薬用化粧品中の医薬組成物の含有量は、ステロイド剤の種類等を勘案して決定できる。
薬用化粧品がステロイド剤を含む場合、薬用化粧品中のグルコース／ステロイド比は、１０〜１０５が好ましく、１０２〜１０４がより好ましく、１０２〜１０３がさらに好ましい。上記範囲内であれば、ステロイド剤の増殖抑制作用がより軽減されて、組織の修復がより促進されやすくなる。加えて、上記範囲内であれば、ステロイド剤の抗炎症作用等の作用が十分に発揮されやすい。
The content of the pharmaceutical composition in the medicated cosmetic product can be determined in consideration of the use and dosage form of the medicated cosmetic product. For example, the glucose concentration in the medicated cosmetic product is preferably 1 to 1000 mM / L, more preferably 10 to 10. The amount is 100 mM / L. Within the above range, production and release of HMGB1 can be further promoted, cell damage can be better prevented, and tissue repair can be further promoted. In the case of containing a medicated cosmetic containing a steroid, the content of the pharmaceutical composition in the medicated cosmetic can be determined in consideration of the type of the steroid.
When the medicated cosmetic contains a steroid, the glucose / steroid ratio in the medicated cosmetic is preferably 10 to 10 5 , more preferably 10 2 to 10 4 , and even more preferably 10 2 to 10 3 . Within the above range, the growth inhibitory action of the steroid agent is further reduced, and tissue repair is more easily promoted. In addition, if it is within the above range, the anti-inflammatory action and the like of the steroid agent are sufficiently exerted.
薬用化粧品は、本発明の効果を阻害しない範囲で、必要に応じて、本発明の医薬組成物以外の任意成分（以下、化粧品任意成分ということがある）を含有できる。
化粧品任意成分としては、例えば、流動パラフィン、セレシン、じろう、ラノリン、ワセリン、セタノール、スクワレン、ホホバ油、ステアリン酸、パルミチン酸、ラウリルアルコール、ステアリルアルコール、セチルアルコール、ミツロウ、メチルポリシロキサン、ジメチルシクロポリシロキサン等の油剤；プロパノール、グリコール、プロピレングリコール、ヒアルロン酸、コラーゲン、ポリエチレングリコール、ヒドロキシステアリン酸コレステリル、グリセリン、ソルビトール等の保湿剤；各種界面活性剤；乳化剤；賦形剤：増粘剤；ＰＨ調整剤；酸化防止剤；色素；香料；紫外線吸収剤等が挙げられる。これらの化粧品任意成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
Medicinal cosmetics can contain optional components other than the pharmaceutical composition of the present invention (hereinafter sometimes referred to as cosmetic optional components) as needed, as long as the effects of the present invention are not impaired.
Cosmetic optional ingredients include, for example, liquid paraffin, ceresin, jiro, lanolin, petrolatum, cetanol, squalene, jojoba oil, stearic acid, palmitic acid, lauryl alcohol, stearyl alcohol, cetyl alcohol, beeswax, methylpolysiloxane, dimethylcyclopolysiloxane Oil agents such as siloxane; humectants such as propanol, glycol, propylene glycol, hyaluronic acid, collagen, polyethylene glycol, cholesteryl hydroxystearate, glycerin, sorbitol; various surfactants; emulsifiers; excipients: thickeners; PH adjustment Agents; antioxidants; pigments; fragrances; ultraviolet absorbers and the like. These cosmetic optional ingredients may be used alone or in combination of two or more.
上述の通り、本発明の医薬組成物は、グルコースを含有するため、細胞障害を効果的に予防でき、各種障害を受けた組織の修復を促進できる。グルコースが細胞障害を予防する機構、組織修復を促進する機構は、次のように考えられる。グルコースが投与されると、細胞質のＩＰ６Ｋ−１キナーゼが活性化し、活性化したＩＰ６Ｋ−１キナーゼが細胞外シグナル調節キナーゼ（ＥＲＫ）を活性化する。活性化したＥＲＫは、核内のＨＭＧＢ１の産生を促進すると共に、ＨＭＧＢ１の細胞外への放出を誘導する。そして、細胞外に放出されたＨＭＧＢ１は、正常細胞の増殖や遊走を促進して、炎症細胞を活性化したり、組織を保護したり、組織を修復したりする。例えば、本発明の医薬組成物を皮膚に塗布すると、皮膚角化細胞又は皮膚線維芽細胞でのＨＭＧＢ１の産生が促進され、産生されたＨＭＧＢ１は、細胞外に放出され、皮膚角化細胞又は上皮細胞の増殖や遊走を促進し、皮膚創傷の治癒を促進できる。 As described above, since the pharmaceutical composition of the present invention contains glucose, it can effectively prevent cell damage and promote the repair of various damaged tissues. The mechanism by which glucose prevents cell damage and the mechanism to promote tissue repair are considered as follows. When glucose is administered, cytoplasmic IP6K-1 kinase is activated and activated IP6K-1 kinase activates extracellular signal-regulated kinase (ERK). Activated ERK promotes the production of HMGB1 in the nucleus and induces the release of HMGB1 extracellularly. HMGB1 released to the outside of the cell promotes proliferation and migration of normal cells, activates inflammatory cells, protects tissues, and repairs tissues. For example, when the pharmaceutical composition of the present invention is applied to the skin, the production of HMGB1 in skin keratinocytes or skin fibroblasts is promoted, and the produced HMGB1 is released extracellularly, and the skin keratinocytes or epithelium is released. It can promote cell proliferation and migration, and promote healing of skin wounds.
加えて、本発明の医薬組成物は、ステロイド剤を含有することで、抗炎症作用に優れると共に、グルコースがステロイド剤の増殖抑制作用を軽減して、細胞障害を効果的に予防でき、各種障害を受けた組織の修復を促進できる。
さらに、グルコース／ステロイド比を特定の範囲とすることで、ステロイド剤の抗炎症作用等の作用をより高度に維持したまま、ステロイド剤の増殖抑制作用を軽減して、細胞障害をより効果的に予防でき、各種障害を受けた組織の修復をより促進できる。
本発明の薬用化粧品は、本発明の医薬組成物を含有するため、細胞障害を効果的に予防でき、各種障害を受けた組織の修復を促進できる。
In addition, the pharmaceutical composition of the present invention is excellent in anti-inflammatory action by containing a steroid agent, and glucose can reduce the growth inhibitory action of the steroid agent to effectively prevent cell damage. Can promote the repair of affected tissues.
Furthermore, by setting the glucose / steroid ratio within a specific range, the anti-inflammatory effect of the steroid agent is maintained at a higher level, and the growth inhibitory effect of the steroid agent is reduced, thereby causing more effective cell damage. It can be prevented and the repair of damaged tissues can be promoted more.
Since the medicinal cosmetics of the present invention contain the pharmaceutical composition of the present invention, it is possible to effectively prevent cell damage and promote the repair of various damaged tissues.
以下、実施例を示して本発明を詳細に説明するが、本発明は以下の記載によって限定されるものではない。 EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description.
（実施例１〜６、比較例１〜４）
１質量％仔牛血清（ＦＢＳ）含有ダルベッコ変性イーグル培地（１％ＦＢＳ−ＤＭＥＭ、ライフテクノロジーズジャパン株式会社製）に、表１の濃度となるようにＬ−グルコースとデキサメサゾン（製品番号：Ｄ４９０２、シグマ−アルドリッチ（Ｓｉｇｍａ−Ａｌｄｏｒｉｃｈ）社製）とを添加し、医薬組成物を含有する培地（以下、試験用培地という）を調製した。各例の試験用培地を用いて、細胞増殖試験を行い、その結果を表１、図１〜２に示す。
(Examples 1-6, Comparative Examples 1-4)
L-glucose and dexamethasone (product number: D4902, Sigma) in 1% by weight calf serum (FBS) -containing Dulbecco's modified Eagle medium (1% FBS-DMEM, Life Technologies Japan Co., Ltd.) so as to have the concentrations shown in Table 1. Aldrich (manufactured by Sigma-Aldrich) was added to prepare a medium containing a pharmaceutical composition (hereinafter referred to as test medium). A cell growth test was performed using the test medium of each example, and the results are shown in Table 1 and FIGS.
＜細胞増殖試験Ａ＞
１％ＦＢＳ−ＤＭＥＭを用い、正常ヒト皮膚角化細胞（単一ドナー由来の初代培養の正常皮膚角化細胞、タカラバイオ株式会社製）を９６穴（ｗｅｌｌ）マイクロプレートに２００００ｃｅｌｌｓ／ｗｅｌｌとなるように播種し、３７℃で２４時間培養した（前培養）。前培養後、各例の試験用培地を前培養に用いた培地と置換し、３７℃で２４時間培養した（本培養）。本培養後、３−（４，５−Ｄｉｍｅｔｈｙｌ−２−ｔｈｉａｚｏｌｙｌ）−２，５−ｄｉｐｈｅｎｙｌｔｅｔｒａｚｏｌｉｕｍ Ｂｒｏｍｉｄｅ（ＭＴＴ）を０．４ｍｇ／ｍＬ含有する１％ＦＢＳ−ＤＭＥＭを試験用培地と置換し、３７℃で４時間培養した（後培養）。後培養後、培地を除去し、Ｄｉｍｅｔｈｙｌ ｓｕｌｆｏｘｉｄｅ１００μＬ／ｗｅｌｌを添加混合して試料液とし、この試料液の吸光度（５５０ｎｍ）を測定してＭＴＴの還元量（α）を求めた。また、本培養を行わない以外は上述の方法と同様にして試料液（コントロール試料液）を調製し、このコントロール試料液の吸光度（５５０ｎｍ）を測定してＭＴＴの還元量（β）を求め、下記（１）式により細胞増殖率を算出した。
細胞増殖率（％）＝還元量（α）÷還元量（β）×１００ ・・・（１）
<Cell proliferation test A>
Using 1% FBS-DMEM, normal human skin keratinocytes (primary cultured normal skin keratinocytes derived from a single donor, manufactured by Takara Bio Inc.) are set to 20000 cells / well in a 96-well microplate. And cultured at 37 ° C. for 24 hours (preculture). After the preculture, the test medium in each example was replaced with the medium used for the preculture, and cultured at 37 ° C. for 24 hours (main culture). After the main culture, 1% FBS-DMEM containing 0.4 mg / mL of 3- (4,5-Dimethyl-2-thiazolyl) -2,5-diphenyltetrazole bromide (MTT) was replaced with the test medium, and the temperature was 37 ° C. For 4 hours (post-culture). After the post-culture, the medium was removed,
Cell proliferation rate (%) = reduction amount (α) ÷ reduction amount (β) × 100 (1)
＜細胞増殖試験Ｂ＞
正常ヒト皮膚角化細胞を正常ヒト皮膚線維芽細胞（単一ドナー由来の初代培養の正常皮膚線維芽細胞、タカラバイオ株式会社製）に換えた以外は、「＜細胞増殖試験Ａ＞」と同様にして、細胞増殖率を求めた。
<Cell proliferation test B>
Same as “<Cell proliferation test A>” except that normal human skin keratinocytes were replaced with normal human skin fibroblasts (primary cultured normal skin fibroblasts derived from a single donor, manufactured by Takara Bio Inc.). Thus, the cell proliferation rate was determined.
図１は、細胞増殖試験Ａの結果を示すグラフであり、図２は、細胞増殖試験Ｂの結果を示すグラフである。
表１、図１〜２に示すように、本発明を適用した実施例１〜３は、細胞増殖率が１００％と略同等又は１００％超となっていた。特に、グルコースを１０〜１００ｍＭ／Ｌ含有する実施例２、３において、細胞増殖率の向上が顕著であった。
一方、グルコース及びデキサメサゾンを含まない比較例１は、細胞増殖試験Ａ及びＢにおいて、細胞増殖率が１００％であった。
実施例１〜３、比較例１の結果から、グルコースを添加することにより、細胞の増殖を促進できることが判った。
比較例２〜４の結果に示すように、デキサメサゾンの含有量の増加に伴い、細胞増殖率が低下していた。この結果から、デキサメサゾンによって正常細胞の増殖が抑制されていることが判った。
細胞増殖試験Ａ及びＢにおいて、グルコース及びデキサメサゾンを含有する実施例４〜６は、実施例４〜６と同量のデキサメサゾンを含有し、かつグルコースを含有しない比較例３に比べて高い細胞増殖率であった。実施例４〜６、比較例３の結果から、正常細胞に対するデキサメサゾンの増殖抑制効果が、グルコースによって軽減されることが判った。
以上の結果から、本発明を適用することで、正常細胞の増殖を促進して、細胞障害を予防したり、各種障害を受けた組織の修復を促進したりできることが判った。
FIG. 1 is a graph showing the results of the cell proliferation test A, and FIG. 2 is a graph showing the results of the cell proliferation test B.
As shown in Table 1 and FIGS. 1-2, in Examples 1 to 3 to which the present invention was applied, the cell proliferation rate was substantially equal to 100% or more than 100%. In particular, in Examples 2 and 3 containing 10 to 100 mM / L of glucose, the improvement in cell growth rate was remarkable.
On the other hand, Comparative Example 1 not containing glucose and dexamethasone had a cell growth rate of 100% in cell proliferation tests A and B.
From the results of Examples 1 to 3 and Comparative Example 1, it was found that the growth of cells can be promoted by adding glucose.
As shown in the results of Comparative Examples 2 to 4, the cell proliferation rate decreased with an increase in the content of dexamethasone. From this result, it was found that proliferation of normal cells was suppressed by dexamethasone.
In cell proliferation tests A and B, Examples 4 to 6 containing glucose and dexamethasone contain the same amount of dexamethasone as Examples 4 to 6 and have a higher cell proliferation rate than Comparative Example 3 containing no glucose. Met. From the results of Examples 4 to 6 and Comparative Example 3, it was found that the growth inhibitory effect of dexamethasone on normal cells was reduced by glucose.
From the above results, it was found that application of the present invention can promote the proliferation of normal cells to prevent cell damage or promote the repair of various damaged tissues.
（実施例７）
グルコース及び正常ヒト皮膚角化細胞を１％ＦＢＳ−ＤＭＥＭに添加し、グルコース濃度が１０ｍＭ／Ｌ、正常ヒト皮膚角化細胞の含有量が１０００００ｃｅｌｌｓ／ｍＬの試料懸濁液を調製した。この試料懸濁液１００μＬをＣＯ２インキュベーター（３７℃）内で２４時間培養した。培養開始前（０時間）、培養開始３時間後、６時間後、１８時間後、２４時間後に上清を回収し、回収した上清中のＨＭＧＢ１濃度をＨＭＧＢ１ ＥＬＩＳＡ Ｋｉｔ ＩＩ（株式会社シノテスト製）で測定した。その結果を図３に示す。
(Example 7)
Glucose and normal human skin keratinocytes were added to 1% FBS-DMEM to prepare a sample suspension having a glucose concentration of 10 mM / L and a normal human skin keratinocytes content of 100,000 cells / mL. 100 μL of this sample suspension was cultured in a CO 2 incubator (37 ° C.) for 24 hours. The supernatant was collected before the start of culture (0 hour), 3 hours, 6 hours, 18 hours, and 24 hours after the start of culture, and the HMGB1 concentration in the collected supernatant was determined to be HMGB1 ELISA Kit II (manufactured by Sinotest Co., Ltd.) Measured with The result is shown in FIG.
（比較例５）
グルコースを含有しない試料懸濁液を用いた以外は、実施例７と同様にして上清中のＨＭＧＢ１濃度を測定した。その結果を図３に示す。
(Comparative Example 5)
The concentration of HMGB1 in the supernatant was measured in the same manner as in Example 7 except that a sample suspension containing no glucose was used. The result is shown in FIG.
図３に示すように、グルコースを添加した実施例７は、比較例５に比べてＨＭＧＢ１濃度が高かった。この結果から、グルコースが正常ヒト皮膚角化細胞からのＨＭＧＢ１の放出を促進することが判った。 As shown in FIG. 3, Example 7 to which glucose was added had a higher HMGB1 concentration than Comparative Example 5. From this result, it was found that glucose promotes the release of HMGB1 from normal human skin keratinocytes.
（実施例８）
グルコース濃度１０ｍＭ／Ｌの１％ＦＢＳ−ＤＭＥＭを調製し、これを試験用培地とした。前培養をしないこと、及びマイクロプレートに１００００ｃｅｌｌｓ／ｗｅｌｌの正常ヒト皮膚角化細胞を播種した以外は、「＜細胞増殖試験Ａ＞」と同様にして細胞増殖率を求め、その結果を図４に示す。
(Example 8)
1% FBS-DMEM having a glucose concentration of 10 mM / L was prepared and used as a test medium. The cell growth rate was determined in the same manner as in “<Cell proliferation test A>” except that no preculture was performed and 10,000 cells / well of normal human keratinocytes were seeded on a microplate. The results are shown in FIG. Show.
（実施例９）
グルコース及び正常ヒト皮膚線維芽細胞を１％ＦＢＳ−ＤＭＥＭに添加し、グルコース濃度が１０ｍＭ／Ｌ、正常ヒト皮膚線維芽細胞の含有量が１０００００ｃｅｌｌｓ／ｍＬの試料懸濁液を調製した。この試料懸濁液を３７℃で、２４時間培養した後、上清（培養上清）を採取した。採取した培養上清１００μＬを正常ヒト皮膚角化細胞１００００ｃｅｌｌｓに加え、３７℃で２４時間培養した。培養後、実施例８と同様にして細胞増殖率を求め、その結果を図４に示す。
Example 9
Glucose and normal human skin fibroblasts were added to 1% FBS-DMEM to prepare a sample suspension having a glucose concentration of 10 mM / L and a normal human skin fibroblast content of 100,000 cells / mL. This sample suspension was cultured at 37 ° C. for 24 hours, and then the supernatant (culture supernatant) was collected. 100 μL of the collected culture supernatant was added to 10000 cells of normal human skin keratinocytes and cultured at 37 ° C. for 24 hours. After the cultivation, the cell proliferation rate was determined in the same manner as in Example 8, and the results are shown in FIG.
（参考例１）
さらにニワトリ抗ＨＭＧＢ１ポリクローナル抗体（ＩｇＹフラクション）を１０μｇ／ｍＬとなるように試験用培地に添加した以外は、実施例９と同様にして細胞増殖率を求め、その結果を図４に示す。
(Reference Example 1)
Furthermore, except that a chicken anti-HMGB1 polyclonal antibody (IgY fraction) was added to the test medium at 10 μg / mL, the cell growth rate was determined in the same manner as in Example 9, and the results are shown in FIG.
（比較例６）
グルコースを添加しない以外は、実施例８と同様にして細胞増殖率を求め、その結果を図４に示す。
(Comparative Example 6)
The cell growth rate was determined in the same manner as in Example 8 except that glucose was not added, and the results are shown in FIG.
図４に示すように、試験用培地にグルコースを添加した実施例８は、細胞増殖率が１１０％であった。加えて、培養上清を添加した実施例９は、細胞増殖率が１４２％であった。即ち、培養上清を添加することにより、正常ヒト皮膚角化細胞の増殖がより促進された。
一方、グルコース及び培養上清を添加しなかった比較例６は、細胞増殖率が１００％であった。
さらに、抗ＨＭＧＢ１抗体を添加した参考例１は、細胞増殖率が１０６％であり、実施例９に比べ細胞増殖率が低かった。即ち、ＨＭＧＢ１を不活化させることで、正常ヒト皮膚角化細胞の増殖が抑制された。実施例８〜９、参考例１の結果から、培養上清にはグルコースの存在により放出されたＨＭＧＢ１が含まれ、このＨＭＧＢ１によって正常ヒト皮膚角化細胞の増殖が促進されることが判った。
図３、４の結果から、グルコースは正常ヒト皮膚線維芽細胞からのＨＭＧＢ１の放出を誘導し、放出されたＨＭＧＢ１は正常ヒト皮膚角化細胞の増殖を促進することが判った。
そして、本発明を適用することで、正常細胞の増殖を促進し、組織の修復を促進できることが判った。
As shown in FIG. 4, in Example 8 in which glucose was added to the test medium, the cell growth rate was 110%. In addition, Example 9 to which the culture supernatant was added had a cell growth rate of 142%. That is, the growth of normal human skin keratinocytes was further promoted by adding the culture supernatant.
On the other hand, Comparative Example 6 to which glucose and culture supernatant were not added had a cell growth rate of 100%.
Further, Reference Example 1 to which the anti-HMGB1 antibody was added had a cell growth rate of 106%, which was lower than that of Example 9. That is, by inactivating HMGB1, the growth of normal human skin keratinocytes was suppressed. From the results of Examples 8 to 9 and Reference Example 1, it was found that the culture supernatant contained HMGB1 released due to the presence of glucose, and this HMGB1 promoted the growth of normal human skin keratinocytes.
From the results of FIGS. 3 and 4, it was found that glucose induces the release of HMGB1 from normal human skin fibroblasts, and the released HMGB1 promotes the proliferation of normal human skin keratinocytes.
And it was found that by applying the present invention, normal cell proliferation can be promoted and tissue repair can be promoted.
（実施例１０）
グルコース濃度１０ｍＭ／Ｌの１％ＦＢＳ−ＤＭＥＭを試験用培地とし、この試験用培地を細胞遊走チャンバー（Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ社製）の下層に添加した。１０００００個の正常ヒト皮膚角化細胞をフィルター（８μｍポアサイズ、Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ社製）付きインサートに播種した。播種されたインサートを２４ウェルプレートに載置し、３７℃、５体積%ＣＯ２環境下で２時間培養した。フィルター上層の細胞を綿棒で擦り取り、下層の細胞をメタノールで固定後、ヘマトキシリン染色を行った。無作為に選んだ５視野（倍率×２００）の細胞数の平均を本例の遊走細胞数とした。後述する比較例７で測定された遊走細胞数を基準細胞遊走数とし、下記（２）式により細胞遊走能を求め、その結果を図５に示す。
(Example 10)
1% FBS-DMEM with a glucose concentration of 10 mM / L was used as a test medium, and this test medium was added to the lower layer of a cell migration chamber (Becton Dickinson). 100,000 normal human skin keratinocytes were seeded on an insert with a filter (8 μm pore size, manufactured by Becton Dickinson). The seeded insert was placed in a 24-well plate and cultured for 2 hours at 37 ° C. in a 5% by volume CO 2 environment. The cells in the upper layer of the filter were scraped with a cotton swab, and the cells in the lower layer were fixed with methanol and then stained with hematoxylin. The average number of cells in five randomly selected fields (magnification × 200) was taken as the number of migrating cells in this example. The number of migratory cells measured in Comparative Example 7 described later was used as the reference cell migration number, and the cell migration ability was determined by the following formula (2), and the results are shown in FIG.
細胞遊走能（％）＝各例の細胞遊走数÷基準細胞遊走数×１００ ・・・（２） Cell migration ability (%) = cell migration number in each case / reference cell migration number × 100 (2)
（実施例１１）
グルコース及び正常ヒト皮膚線維芽細胞を１％ＦＢＳ−ＤＭＥＭに添加し、グルコース濃度が１０ｍＭ／Ｌ、正常ヒト皮膚線維芽細胞の含有量が１０００００ｃｅｌｌｓ／ｍＬの懸濁液を調製した。この懸濁液を３７℃で、２４時間培養した後、上清（培養上清）を採取した。この培養上清５００μＬとグルコース濃度１０ｍＭ／Ｌの１％ＦＢＳ−ＤＭＥＭ５００μＬとを混合して試験用培地とした以外は、実施例１０と同様にして細胞遊走能を求めた。その結果を図５に示す。
(Example 11)
Glucose and normal human skin fibroblasts were added to 1% FBS-DMEM to prepare a suspension having a glucose concentration of 10 mM / L and a normal human skin fibroblast content of 100,000 cells / mL. This suspension was cultured at 37 ° C. for 24 hours, and then the supernatant (culture supernatant) was collected. Cell migration ability was determined in the same manner as in Example 10 except that 500 μL of this culture supernatant and 500 μL of 1% FBS-DMEM having a glucose concentration of 10 mM / L were mixed to obtain a test medium. The result is shown in FIG.
（参考例２）
さらに抗ＨＭＧＢ１抗体を１０μｇ／ｍＬとなるように試験用培地に添加した以外は、実施例１１と同様にして細胞遊走能を求め、その結果を図５に示す。
(Reference Example 2)
Further, cell migration ability was determined in the same manner as in Example 11 except that anti-HMGB1 antibody was added to the test medium so as to be 10 μg / mL, and the results are shown in FIG.
（比較例７）
グルコースを添加しない以外は、実施例１０と同様にして細胞遊走能を求め、その結果を図５に示す。
(Comparative Example 7)
Cell migration ability was determined in the same manner as in Example 10 except that glucose was not added, and the results are shown in FIG.
図５に示すように、試験用培地にグルコースを添加した実施例１０は、細胞遊走能が１０２％であった。加えて、グルコースを加えた試料懸濁液の培養上清を添加した実施例１１は、細胞遊走能が１７１％であった。即ち、培養上清を添加することにより、正常ヒト皮膚角化細胞の遊走が誘導された。
一方、グルコース及び培養上清を添加しなかった比較例７は、細胞遊走能が１００％であった。
さらに、抗ＨＭＧＢ１抗体を添加した参考例２は、細胞遊走能が１１６％であり、実施例１１に比べ細胞遊走能が低かった。即ち、ＨＭＧＢ１を不活化させることで、正常ヒト皮膚角化細胞の遊走がより促進された。実施例１０〜１１、参考例２の結果から、培養上清にはグルコースの存在により放出されたＨＭＧＢ１が含まれ、このＨＭＧＢ１によって正常ヒト皮膚角化細胞の遊走が促進されることが判った。
図３、５の結果から、グルコースは正常ヒト皮膚線維芽細胞からのＨＭＧＢ１の放出を誘導し、放出されたＨＭＧＢ１は正常ヒト皮膚角化細胞の遊走を促進することが判った。
そして、本発明を適用することで、正常細胞の遊走を促進し、組織の修復を促進できることが判った。
As shown in FIG. 5, Example 10 in which glucose was added to the test medium had a cell migration ability of 102%. In addition, Example 11 to which the culture supernatant of the sample suspension added with glucose was added had a cell migration ability of 171%. That is, the migration of normal human skin keratinocytes was induced by adding the culture supernatant.
On the other hand, in Comparative Example 7 in which glucose and culture supernatant were not added, the cell migration ability was 100%.
Furthermore, Reference Example 2 to which the anti-HMGB1 antibody was added had a cell migration ability of 116%, which was lower than that of Example 11. That is, inactivation of HMGB1 further promoted migration of normal human skin keratinocytes. From the results of Examples 10 to 11 and Reference Example 2, it was found that the culture supernatant contained HMGB1 released due to the presence of glucose, and that migration of normal human skin keratinocytes was promoted by this HMGB1.
From the results of FIGS. 3 and 5, it was found that glucose induces the release of HMGB1 from normal human skin fibroblasts, and the released HMGB1 promotes the migration of normal human skin keratinocytes.
And it was found that application of the present invention can promote migration of normal cells and promote tissue repair.
（実施例１２）
グルコース含有量１．９ｍｏｌ／Ｌ、ステロイド（リン酸デキサメタゾンナトリウム）含有量０．０９６ｍｏｌ／Ｌを含有する水溶液を調製し、これを外用薬とした。
皮膚全体（顔部、上半身、下半身、指（手・足））に皮膚掻痒、色素沈着、苔癬化が見られる患者（２０歳代男性）に対し、前記外用薬を患部に１回／１日塗布した。その結果、外用薬の塗布を開始した翌日には皮膚掻痒感がなくなり、外用薬の塗布を開始した３か月後には色素沈着、皮膚苔癬化が消失した。
外用薬の塗布を開始する前において、患者の血清中ＩｇＥ濃度は５５００、患者のｔｈｙｍｕｓ ａｎｄ ａｃｔｉｖａｔｉｏｎ−ｒｅｇｕｌａｔｅｄ ｃｈｅｍｏｋｉｎｅ（ＴＡＲＣ）は５３００であった。外用薬の塗布開始３ヶ月後には、患者の血清中ＩｇＥ濃が２７００〜２８００、ＴＡＲＣが１７０と低値となり、アレルギー反応の顕著な改善が認められた。なお、血清中ＩｇＥ濃度、ＴＲＡＣは共にアレルギー疾患の重症度の指標となるものである。
(Example 12)
An aqueous solution containing a glucose content of 1.9 mol / L and a steroid (dexamethasone sodium phosphate) content of 0.096 mol / L was prepared and used as an external medicine.
For patients (male in their 20s) who have skin pruritus, pigmentation, and lichenification on the entire skin (face, upper body, lower body, fingers (hands and feet)), apply the above topical medicine once to the affected area. It was applied on the day. As a result, the skin irritation disappeared the day after the start of the application of the external medicine, and pigmentation and skin lichenification disappeared 3 months after the start of the application of the external medicine.
Prior to the start of application of the topical drug, the patient's serum IgE concentration was 5500, and the patient's thymus and activation-regulated chemokine (TARC) was 5300. Three months after the start of application of the external medicine, the patient's serum IgE concentration decreased to 2700-2800 and TARC 170, indicating a marked improvement in allergic reaction. The serum IgE concentration and TRAC are both indicators of the severity of allergic diseases.
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| KR1020147020143A KR101514257B1 (en) | 2012-01-23 | 2013-01-22 | Pharmaceutical Composition and Quasi-Drug Cosmetic Using Same |
| EP13740840.7A EP2808025B1 (en) | 2012-01-23 | 2013-01-22 | Pharmaceutical composition and quasi-drug cosmetic using same |
| PCT/JP2013/051159 WO2013111729A1 (en) | 2012-01-23 | 2013-01-22 | Pharmaceutical composition and quasi-drug cosmetic using same |
| TW102102452A TWI468184B (en) | 2012-01-23 | 2013-01-23 | Pharmaceutical composition and medical cosmetics |
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| JP2015218137A (en) * | 2014-05-16 | 2015-12-07 | 株式会社Cac | IgE inhibitor |
| WO2018181599A1 (en) | 2017-03-31 | 2018-10-04 | 株式会社Cac | Agent for enhancing skin barrier, medicinal composition, medicated cosmetic and beauty care method |
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| TW201332580A (en) | 2013-08-16 |
| KR101514257B1 (en) | 2015-04-24 |
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| HK1204556A1 (en) | 2015-11-27 |
| EP2808025B1 (en) | 2016-07-13 |
| EP2808025A4 (en) | 2014-12-17 |
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